# US 10,500,161 B2 · Timed, pulsatile release systems

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- Number: US 10,500,161 B2
- Document ID: US10500161B2
- Status: Granted
- Kind: B2
- Application number: 16/037,890
- Filed: 2018-07-17
- Published: 2019-03-14
- Granted: 2019-12-10
- Earliest claimed: 2005-05-02
- Assignees: Adare Pharmaceuticals, Inc.
- Applicants: Adare Pharmaceuticals, Inc.
- Inventors: Gopi M. Venkatesh
- Web page: https://patentgrep.com/patent/US10500161B2

## CPC

- A61K 9/5073: {having two or more different coatings optionally including drug-containing subcoatings}
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 9/1676: {having a drug-free core with discrete complete coating layer containing drug (adsorbates of liquid drug formulations on inert powders without simultaneous granulation step A61K9/141; with further drug-free outer coating A61K9/5078; drug conjugated to non-active particles A61K47/6921)}
- A61K 9/2081: {with microcapsules or coated microparticles according to A61K9/50}
- A61K 9/4808: {characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release (capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084)}
- A61K 9/5042: {Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose}
- A61K 9/5047: {Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose}
- A61K 9/5078: {with drug-free core}
- A61K 9/5084: {Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs (tablets containing such a mixture A61K9/2077)}
- A61K 9/5089: {Processes}
- A61K 31/426: 1,3-Thiazoles
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/08: for nausea, cinetosis or vertigo; Antiemetics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 11/06: Antiasthmatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 21/02: Muscle relaxants, e.g. for tetanus or cramps
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

A unit multiparticulate dosage form for delivering one or more basic, active pharmaceutical ingredients into the body in need of such medications to achieve target PK (pharmacokinetics) profiles is described. The dosage form comprises one or more multicoated drug particles (beads, pellets, mini-/micro-tablets) having a barrier coating and a lag-time coating. Each Timed Pulsatile Release (TPR) bead population exhibits pre-determined lag-time followed by differing release characteristics. The composition and thickness of the barrier coating, composition and thickness of the lag-time coating, ratio of IR beads to one or more TPR bead populations and total dose may be varied depending on the alkalinity, pH-dependent solubility and elimination half-life of the active ingredients to achieve target PK profiles (suitable for a once or twice daily dosing regimen) in patients in need of such medications.

## Claims

### Claim 1

A multiparticulate drug delivery formulation comprising a first and a second population of timed, pulsatile release (TPR) beads, wherein at least one of the first and the second population of TPR beads comprises:
i. a core particle comprising an active pharmaceutical ingredient or a pharmaceutically acceptable salt thereof; and
ii. an outer lag-time coating comprising a water-insoluble polymer in combination with at least one enteric polymer,
wherein:
the first population of TPR beads provides a lag time of at least about 3 hours before onset of drug release and the second population of TPR beads provides a lag time of at least about 6 hours before onset of drug release,
when tested for dissolution using Apparatus 1 (Baskets@ 100 rpm) or 2 (Paddles @ 50 rpm) and a two-stage dissolution medium (first two hours in 700 mL of 0.1 N HCl and thereafter in 900 mL of phosphate buffer at pH 6.8).

### Claim 2 (depends on 1)

The multiparticulate drug delivery formulation of claim 1, wherein said enteric polymer is selected from the group consisting of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose succinate, polyvinyl acetate phthalate, pH-sensitive methacrylic acid-methylmethacrylate copolymers, shellac, and mixtures thereof.

### Claim 3 (depends on 1)

The multiparticulate drug delivery formulation of claim 1, wherein said the enteric polymer is a mixture of pH-sensitive methacrylic acid-methylmethacrylate copolymers.

### Claim 4 (depends on 1)

The multiparticulate drug delivery formulation of claim 1, wherein said water-insoluble polymer is selected from the group consisting of ethylcellulose, cellulose acetate, cellulose acetate butyrate, polyvinyl acetate, methylmethacrylate ester polymers, neutral copolymers based on ethylacrylate and methylmethacrylate, copolymers of acrylic and methacrylic acid esters, and mixtures thereof.

### Claim 5 (depends on 1)

The multiparticulate drug delivery formulation of claim 1, wherein said water-insoluble polymer is a neutral copolymer based on ethylacrylate and methylmethacrylate.

### Claim 6 (depends on 1)

The multiparticulate drug delivery formulation of claim 1, wherein the outer lag-time coating comprises a plasticizer.

### Claim 7 (depends on 1)

The multiparticulate drug delivery formulation of claim 1, further comprising immediate release beads, each immediate release bead comprising a core particle comprising said active pharmaceutical ingredient or a pharmaceutically acceptable salt thereof; wherein said immediate release beads release not less than about 90% of said active pharmaceutical ingredient contained therein within the first hour after oral administration of the multiparticulate drug delivery formulation.

### Claim 8 (depends on 1)

The multiparticulate drug delivery formulation of claim 1, wherein the drug-containing core particle in the TPR bead comprises:
i. an inert particle coated with the drug and optionally a polymeric binder; or
ii. a pellet, or mini- or micro-tablet, a microgranule, or a granular particle containing the drug and optionally a polymeric binder.

### Claim 9 (depends on 8)

The multiparticulate drug delivery formulation of claim 8, wherein the said optional polymeric binder is selected from the group consisting of polyvinylpyrrolidone, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, corn starch, pregelatinized starch, and mixtures thereof.

### Claim 10 (depends on 7)

The multiparticulate drug delivery formulation of claim 7, wherein the drug-containing core particle in the immediate release bead comprises:
i. an inert particle coated with the drug and optionally a polymeric binder; or
ii. a pellet, or mini- or micro-tablet, a microgranule, or a granular particle containing the drug and optionally a polymeric binder.

### Claim 11 (depends on 10)

The multiparticulate drug delivery formulation of claim 10, wherein the said optional polymeric binder is selected from the group consisting of polyvinylpyrrolidone, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, corn starch, pregelatinized starch, and mixtures thereof.

### Claim 12 (depends on 8)

The multiparticulate drug delivery formulation of claim 8, wherein the said core particle further comprises a seal coating layer comprising hydroxypropyl methylcellulose or hydroxypropylcellulose.

### Claim 13 (depends on 10)

The multiparticulate drug delivery formulation of claim 10, wherein the said core particle further comprises a seal coating layer comprising hydroxypropyl methylcellulose or hydroxypropylcellulose.

### Claim 14 (depends on 1)

The multiparticulate drug delivery formulation of claim 1, wherein the ratio of said water insoluble polymer to said at least one enteric polymer in said outer lag-time coating ranges from about 10:1 to about 1:3.

### Claim 15 (depends on 1)

The multiparticulate drug delivery formulation of claim 1, wherein the ratio of said water insoluble polymer to said enteric polymer in said outer lag-time coating ranges from about 3:1 to about 1:1.

### Claim 16 (depends on 1)

The multiparticulate drug delivery formulation of claim 1, wherein said drug delivery formulation takes the form of a capsule, a conventional tablet, or an orally disintegrating tablet.

### Claim 17 (depends on 1)

The multiparticulate drug delivery formulation of claim 1, wherein said outer lag-time coating consists essentially of a water-insoluble polymer in combination with an enteric polymer.

### Claim 18 (depends on 1)

The multiparticulate drug delivery formulation of claim 1, further comprising an inner barrier coating.

### Claim 19 (depends on 18)

The multiparticulate drug delivery formulation of claim 18, wherein said inner barrier coating consists essentially of an enteric polymer.

### Claim 20 (depends on 1)

The multiparticulate drug delivery formulation of claim 1, wherein the amount of said outer lag-time coating is about 1.5% to 60% by weight of said timed, pulsatile release beads.

### Claim 21 (depends on 1)

The multiparticulate drug delivery formulation of claim 1, wherein the amount of said outer lag-time coating is about 30% to 60% by weight of said timed, pulsatile release beads.

### Claim 22 (depends on 1)

The multiparticulate drug delivery formulation of claim 1, wherein the amount of said outer lag-time coating is about 40% to 55% by weight of said timed, pulsatile release beads.

### Claim 23 (depends on 1)

The multiparticulate drug delivery formulation of claim 1, wherein the first population of TPR beads has a lag time of 3-4 hours.

### Claim 24 (depends on 1)

The multiparticulate drug delivery formulation of claim 1, wherein the second population of TPR beads has a lag time of from 6-9 hours.

### Claim 25 (depends on 1)

The multiparticulate drug delivery formulation of claim 1, wherein the first and second populations of TPR beads exhibit different in vivo plasma concentration profiles of the active pharmaceutical ingredient or a pharmaceutically acceptable salt thereof upon oral administration.